It appears that patients with diabetes mellitus are predisposed to gram-negative infections. Anecdotal evidence suggests that septicemia in these individuals is associated with an increased insulin requirement; however, systematic studies concerning changes in insulin sensitivity in the diabetic during infection are lacking. The long-term goal of this research is to define mechanisms responsible for the increased insulin resistance following bacterial infection in diabetic patients, compare these to changes seen in nondiabetic individuals during sepsis, and ultimately to identify the consequences of these changes on the recovery of both patient populations. Two working hypotheses will be considered: (1) gram-negative infection further impairs both glucose- and insulin- mediated regulation of glucose production and utilization in chronic diabetes, and (2) the sepsis-induced increase in circulating concentrations of counterregulatory hormones are responsible for the increased insulin resistance in sepsis. These experiments will utilize chronically catheterized conscious nondiabetic and diabetic (streptozotocin) rats. Sepsis will be induced in both groups by subcutaneous injection of live E. coli. Hypothesis 1 will be addressed by specific aims which determine glucose kinetics, hepatic and muscle glycogen reserves and the activity of rate-controlling enzymes of glycogen metabolism in the basal state. Second, insulin resistance will be quantitated in vivo by determining the rate of glucose disposal using euglycemic and hyperglycemic insulin clamps. These studies will also provide information on the balance between glycogen synthesis and glucose output by the liver by determining the fate of gluconeogenically derived glucose-6-phosphate. Third, in vivo insulin dose-response curves for selected individual tissues will be determined using 3H-2-deoxyglucose. Hypothesis 2 will be tested by using glycemic clamp techniques and selectively lowering the plasma concentration (e.g., glucagon, corticosterone and growth hormone) or blocking the action (e.g., catecholamines) of one of the counterregulatory hormones. These studies will provide definitive information on whole body and tissue insulin sensitivity in sepsis and diabetes and the interaction of these two conditions. It will also aid in understanding the factors which make diabetics more susceptible to gram-negative infections.